The extracellular adenosine receptor has a modulatory role in the nervous, circulatory, endocrine and immunological systems. The prospect of harnessing these effects specifically for therapeutic purposes is attractive. Recently this project has focused on the effects of adenosine agonists and antagonists in the central nervous system and on the possibility of therapeutics for treating neurodegenerative diseases. Chronic treatment with an adenosine agonist improves spatial memory retention and acquisition and indicates necessity of further studies directed towards Alzheimers disease. Neuroprotective effects of acutely administered A1 receptor agonists and chronically administered A1 receptor antagonists have been demonstrated in a model of global ischemia in gerbils. Adenosine agonists prevent convulsions in several chemical and electrical seizure models and protect against excitotoxic neurodegeneration agonists and antagonists suggests some adaptation (sensitization by antagonists/desensitization by agonists) of the mechanism of receptor activation, either at the level of receptor or second messenger. We have synthesized the first selective A3 receptor agonists and antagonists. An A3 agonist, administered chronically, proved to be highly cerebro-protective in an ischemic model in gerbils. A3 agonists cause morpholigical and biochemical changes in astroglial cells. An acutely administered A3 agonist, Cl-IB-MECA, was cardioprotective in cell culture, through the selective activation of A3 receptors. The protection was blocked in the presence of a selective A3 receptor antagonist. A link between A3 receptors and programmed cell death has been discovered, and we are investigating this link mechanistically. In summary, highly selective adenosine analogues may have therapeutic potential in treatment of cerebral ischemia/stroke and possibly other neurodegenerative disorders as well. Since the three major subtypes of adenosine receptors have been cloned it has been possible to conduct molecular modeling of the receptor protein, based on sequence analyses and computerized energy minimizations. It is proposed that modulation of A2B and A3 receptors may be useful in treating asthma and inflammatory diseases. The pharmacolgical properties of novel xanthines developed in our lab that act as selective A2B receptor antagonists are being explored. - stroke, asthma, myocardial infarction, xanthines, organic chemistry, radioligand binding, receptor pharmacology, nucleosides